Neuronal cell survival and differentiation is dependent upon many different growth factors, of which nerve growth factor (NGF) has provided the best evidence for a physiological role during development. NGF's effects are restricted to sensory and sympathetic neurons, and basal fore brain cholinergic neurons. These limited populations are responsive, due to the expression of a functional NGF receptor complex, Consisting of two transmembrane glycoproteins, the low affinity p75 NGF receptor and the trk receptor tyrosine kinase. The primary goals of this grant are to define the unique structural features of these two receptors, and the intracellular signaling machinery that is triggered upon NGF binding to responsive cells. NGF represents a family of related factors, including BDNF, NT-3, NT-4 and NT-5 which function during development of the central and peripheral nervous systems. Considerable promiscuity exists between neurotrophin factors and their receptors, requiring specific discriminatory mechanisms. This proposal will determine where the specificity of signal transduction is encoded for NGF, distinctive from other growth factors. Receptor associated molecules specific to NGF will be identified and cloned. Since the trk NGF receptor can potentially behave as an oncogene, these studies will also address the molecular and biochemical events that dictate whether a cell undergoes proliferation or differentiation. This investigation will have implications for mechanisms of neoplastic transformation, as well as survival and differentiation of neuronal cell populations, which will ultimately bear upon our understanding of many neurodegenerative diseases, such as Parkinson's and Alzheimer's dementia.